Project Summary This proposal is a new application for a multiple-PI R21. The goal of the application is to define a role for the thromboxane-prostanoid receptor (TP-R, a G-protein coupled receptor involved in eicosanoid metabolism) on the adipose-liver axis, specifically in the setting of alcoholic and non-alcoholic fatty liver disease (AFLD and NAFLD). Of special interest to us is the examination of a link between TP-R function and its involvement in the process of adipose tissue (AT) browning; AT browning promotes thermogenesis and alleviates some of the detrimental pathologies seen in NAFLD and AFLD. While TP-Rs are known to play a role in the pathophysiology of several chronic inflammatory diseases such as cardiovascular disease and certain autoimmune diseases, very little is known regarding their role in promoting obesity- and alcohol-related disorders. In our proposed studies, we will be using animal models where we will induce liver injury using a high-fat diet, an ethanol-containing diet, or a combination of both (ethanol administration in addition to high fat). Both NAFLD and AFLD are characterized by impaired hepatic lipid metabolism, and it is now known that the combination of obesity with heavy drinking exacerbates liver injury, with progression to steatohepatitis. Preliminary data from our laboratories have examined NAFLD and its resultant pathologies in mice, focusing on a link between TP-R and AT, and how functional TP-R contributes to liver injury. Our preliminary data in a mouse model of global TP-R deficiency showed that the TP-R-/- mice gain less body weight, show increased energy expenditure, and increased markers of AT browning, and an improvement in NAFLD. In the present study, we hypothesize that mice lacking TP-R will be, at least partially, protected from AFLD and/or obesity due to increased energy expenditure via altered AT function. Our novel findings support our central hypothesis that blocking TP-R function will promote adipose browning and fatty acid oxidation in AT which, in turn, will ameliorate ethanol and/or obesity-induced liver injury. We have proposed two specific aims; in Aim 1, we will define the role of TP-R in modulating AT function and the crosstalk between AT and liver during ethanol- and/or obesity-induced liver injury in mice. In Aim 2, we will examine a specific role of TP-R in adipose tissue by studying adipocyte-specific TP-R, and its role in mediating ethanol and/or obesity-induced liver injury in mice. The two principal investigators involved in this project have complementary strengths; one is a long-time expert in alcohol-induced liver damage (Casey), and the other is a new investigator with expertise in adipose tissue and metabolic diseases (Viswanathan). Overall, findings obtained from these studies will provide insight into the mechanisms by which a combination of obesity and ethanol promotes liver injury and the impact of a novel AT-targeted approach in ameliorating AFLD and NAFLD.